The overall, long-term goal of our work is to prevent cutaneous malignant melanoma (CMM), the second fastest increasing cancer in incidence in the U.S.A. If not surgically cured, this malignancy is nearly always fatal. The objective of this proposal is to use measurement of human melanocyte proliferation and differentiation as intermediate endpoint markers for malignant progression to melanoma. Using this approach convincing scientific rationale for the choice of a chemopreventive agent to be used in a clinical prevention trial of CMM will be obtained. The specific aims to achieve this objective include: 1) measurement of proliferative and differentiation characteristics of melanocytes obtained from normal human foreskin, benign acquired moles, and dysplastic nevi; 2) identification of a compound or group of compounds which favorably modulate the proliferative and differentiation features of melanocytes; 3) performance of a phase I trial of the selected chemoprevention agent. Specific aim #1 will be pursued by measuring biochemical differentiation and proliferation properties of melanocytes from foreskin, benign moles, and dysplastic nevi. These markers represent key biologic properties including number of proliferating and differentiating cells as well as critical enzymes that may be involved in the regulation of melanocyte proliferation including protein kinase C (PKC) and ornithine decarboxylase (ODC). Specific aim #2 will be pursued under the assumption that agents known to alter melanocyte proliferation and/or differentiation are likely candidates for chemoprevention agents. Four classes of potential chemopreventive agents which are ready for a trial will be tested and include: signal transduction membrane modulators (inhibitors of phosphatidylinositol metabolism, protein kinase C activation and endogenous prostaglandin synthesis), polyamine synthesis inhibitors, retinoids, and carotenoids. Selected intermediate endpoint markers of proliferation and differentiation will be monitored to assess the effectiveness of the candidate chemoprevention agents. The work proposed in this grant application will lead to identification of chemopreventive agents that block melanocyte proliferation and enhance differentiation. Based on these results, a two- part (dose finding, followed by chronic evaluation) phase I chemoprevention trial will be performed. Subsequently, a randomized phase III chemoprevention trial will be proposed using individuals at high risk for CMM.